The insulin resistant syndrome complicated by disorder of carbohydrate and/or lipid metabolism and hypertension attracts attention as a multi-risk group of high incidence of ischemic heart disease. The insulin resistant syndrome is found in most of patients suffering from obesity and non insulin-dependent diabetes mellitus (NIDDM). The metabolic disorder of lipids herein recognized is the increase in blood triglycerides mainly due to the increase in chylomicron, very low density lipoproteins, and remnant lipoproteins which are the intermediary metabolites thereof, and the decrease in HDL-C (Diabetes, 37, 1595–1607(1988); Arch. Intern. Med., 149, 1514–1520(1989); Diabetes Care, 14, 173–194 (1991)).
Although it has often been disserted that the blood triglyceride level is probably an important risk factor of arteriosclerotic diseases, the clear relevance has not been established. Said level, however, has been reported to be an independent risk factor of ischemic heart disease based on the results obtained recently using arteriography (Circulation, 90, 2230–2235 (1994)).
It is well known that the HDL-C level negatively correlates to incidence of ischemic heart diseases from the results of a lot of epidemiological researches (Circulation, 79, 8–15(1989)). HDL is thought to participate in the reverse cholesterol transport into liver from extrahepatic tissues and demonstrated to have anti-arteriosclerosis effect in animal model experiments (J. Clin. Invest., 85, 1234–1241(1990); Nature, 353, 265–267(1991)).
It has been confirmed that blood total cholesterol level, especially LDL-C level, positively correlates to incidence of ischemic heart diseases and the said incidence can be decreased by lowering the level in a large-scale intervention trial (Lipid Research Clinics Program: JAMA, 251, 351(1984); Lipid Research Clinics Program: JAMA, 251, 365(1984)).
Accordingly, compounds that decrease the blood triglyceride level and LDL-C level, and also increase the HDL-C level or decrease the atherogenic index are useful as a remedy for arteriosclerosis, especially for prevention or treatment of ischemic heart diseases. Further, compounds that improve the insulin resistance are expected to reduce the blood glucose level and blood insulin level, and improve the pathological conditions of complications such as diabetes mellitus, hyperinsulinemia, hypertension and obesity, which can be risk factors of arteriosclerotic diseases, and whereby exert effective preventive or therapeutic activity on arteriosclerosis.
It has been heretofore known that 2-aryl-5-alkyloxazole derivatives or 2-aryl-5-alkylthiazole derivatives of the general formula (A), which have some similarity to the compounds of the present invention have blood lipid lowering effect or blood glucose lowering effect.
wherein:Ring Ar1 is aryl; V is oxygen or sulfur; Ak1 is hydrogen, alkyl or haloalkyl; Ak2 is alkylene; Ak3 is alkylene, alkenylene or alkynylene optionally substituted by alkoxy, alkoxycarbonyl, acylthio, acylamino or aryl; Q is carboxy, 2,4-oxazolinedione-5-yl, 2,4-thiazolinedione-5-yl, or 1,2,4-oxadiazolidine-3,5-dione-2-yl; Ring Ar2 is a group of the formula [B1]or [B2].

For example, compounds included in the general formula (A), namely 2,4-thiazolidinedione derivatives, are reported to have blood lipid lowering effect or blood glucose lowering effect in U.S. Pat. No. 5,532,256, WO96/05186, JP H7-188227, A, JP S61-85372, A and U.S. Pat. No. 5,401,761.
It is described that compounds included in the general formula (A), namely 2,4-oxazolidinedione derivatives, have blood lipid lowering effect or blood glucose lowering effect in JP H9-124623, A, WO95/18125, JP H7-165735, A and U.S. Pat. No. 5,468,762 and JP H8-92228, A.
It is described that compounds included in the general formula (A), namely 1,2,4-oxadiazolidine-3,5-dione derivatives, have blood lipid lowering effect or blood glucose lowering effect in U.S. Pat. No. 5,510,360 and U.S. Pat. No. 5,480,896.
It is described that compounds included in the general formula (A), namely carboxylic acid derivatives, have blood lipid lowering effect or blood glucose lowering effect in WO99/462325, WO98/00137, WO97/31907, WO96/38415, JP H9-323982, A, JP H8-325264, A, JP H5-507920, A, U.S. Pat. No. 5,510,360 and U.S. Pat. No. 5,480,896.
The compound of the general formula (A) is characterized in that it has:    (1) 2-aryl-5-alkyloxazole ring or 2-aryl-5-alkylthiazole ring at one end;    (2) carboxy, 2,4-oxazolinedione-5-yl, 2,4-thiazolinedione-5-yl or 1,2,4-oxadiazolidine-3,5-dione-2-yl at the other end; and    (3) an aromatic ring such as benzene represented by ring Ar2 in the molecule.
Further, EP-A-220573 describes that oxazole derivatives of the general formula (B) show antiarthritic activity.
wherein:Ar3 is substituted phenyl or thienyl; R23 is hydrogen or alkyl; Ak4 is alkylene having 1 to 2 carbon atoms: R24 and R25 are each alkyl; Q1 is carboxy, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoyl.